Featured Sessions

Debaters: Dr. Kenneth L. Hastings1 and Dr. Phil Bentley2 1Hastings Toxicology Consulting LLC, Mount Airy, MD. 2Toxicodynamix International LLC, Hendersonville, NC, and Basel, Switzerland

Each year the SOT and EUROTOX Annual Meetings include a debate that continues a tradition that originated in the early 1990s in which leading toxicologists advocate opposing sides of an issue of significant toxicological importance. This year, our debaters will address the proposition: Toxicology Testing of Drug Combinations Does Not Add Significant Value to Human Risk Evaluation Beyond What is Known for the Individual Agents.
The use of innovative drug combinations—both large and small molecule—in clinical development is increasing. The objective is often to increase efficacy by targeting multiple pathways for the same disease, to improve safety by being able to lower doses of one or more drugs, or to provide more convenient/acceptable therapies to patients. As the number of these clinical combinations rises, there is an increasing need to evaluate their nonclinical safety. At the heart of this evaluation is the question regarding the need for actual animal testing. Global regulatory guidance has provided a framework for the nonclinical safety evaluation of combination products, which considers the need for testing based on such things as the potential for PK or PD interactions, overlapping toxicology profiles, extent of toxicology characterization of the individual agents and their margins of safety, human clinical experience with the individual agents, and the stage of clinical development of each agent. The guidance applies not only to fixed dose combinations but co-packaged and co-use as well. Unless there is clinical experience with the combination and that combination involves two late stage (Phase 3, Marketed) entities, nonclinical repeat dose toxicity studies up to 90 days are recommended. This broad recommendation is inconsistent with the principles of the 3Rs for reduction, refinement, and replacement in animal experimentation. Conversely, the potential for unexpected safety events with novel, targeted therapies is a clear clinical concern. The debaters will discuss the evidence regarding whether the information gathered in nonclinical combination studies provides clear benefit in the overall risk evaluation for clinical combinations.
Regardless of framework differences and personal convictions, each scientific debate delegate will present relevant evidence and compelling scientific arguments to persuade and appeal to the audience in order to obtain the approval or rejection of the motion.